EULAR: Etanercept Valuable for Juvenile Arthritis but New Risk Suggested

Action Points

Explain to interested patients that etanercept is FDA approved for adults with rheumatoid arthritis and for older children with juvenile idiopathic arthritis, but not for children under six.

Explain that rare side effects of drugs are often not identified until they have been on the market for a period of time.

Explain that the apparently high incidence of IBD following etanercept treatment could be associated with the arthritis rather than the drug.

Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

COPENHAGEN, June 17 -- Etanercept (Enbrel) appeared at least as safe and effective in toddlers with juvenile idiopathic arthritis as in older children, an Italian researcher said here.

But a separate study suggested that the drug may have a rare but serious side effect when given to children.

Analysis of registry data on 1,515 juvenile arthritis patients treated with etanercept identified 18 who had developed inflammatory bowel disease, Nico M. Wulffraat, MD, of the University Medical Center Utrecht in the Netherlands reported here at the European League Against Rheumatism (EULAR) annual meeting.

Dr. Wulffraat said the incidence rate suggested by these data -- about 500 per 100,000 patients per year -- is 100 times greater than in the general pediatric population.

But he stopped short of recommending against the drug for children with inflammatory arthritis, noting that the registry data were not wholly reliable.

The Italian study is one of the first to examine use of etanercept, which blocks activity of tumor necrosis factor, in toddler-age children.

Etanercept is not approved for children under 6 in the U.S. or for children younger than 4 in Europe.

In 33 children younger than 4 who had not responded to nonbiologic treatments, six months of etanercept treatment led to ACR70 responses in 42% and ACR50 responses in 63%, reported Antonella Insalaco, MD, of Ospedale Pediatrico Bambino GesÃ¹ in Rome.

At last follow-up, up to 86 months after starting the drug, 75% of patients had ACR70 responses and 83% met ACR50 criteria -- representing 70% and 50% reductions in disease severity by the American College of Rheumatology's scoring system.

"Etanercept results in similar efficacy in inducing and maintaining disease remission" in children younger than 4 compared with older children, Dr. Insalaco said.

She added that the safety profile also appeared similar, but the findings needed to be confirmed in larger trials.

More than half the children in her study had oligoarticular disease and about one-fifth had polyarticular arthritis. Mean duration of disease was 12 months (range 1 to 41).

Etanercept was administered at 0.8 to 1 mg/kg per week for a mean of 23 months (range six to 86).

Dr. Insalaco said 12% of the children had some adverse event, mostly mild.

Four children developed viral infections, including one case of cytomegalovirus and three varicella-zoster infections.

One of the latter turned serious, with necrotizing fasciitis requiring hospitalization. The child survived and etanercept was restarted after a temporary stop, Dr. Insalaco said.

Marieke Otten, MD, a pediatric rheumatologist at Erasmus Medical Center in Rotterdam in the Netherlands, commented that the results weren't surprising.

She said her institution had already begun using etanercept in very young children with juvenile arthritis.

"We only have 11 children so far but we've seen the same results," said Dr. Otten.

But that enthusiasm could be tempered if the findings by Dr. Wulffraat and his colleagues are confirmed.

The researchers examined registry data on children receiving etanercept in five European countries, contacting patients' individual physicians when necessary to obtain additional data.

Of the 18 patients they identified from the registry information, data were too incomplete for evaluation in seven. They also found one additional child developing IBD while on etanercept who was not included in the registries, but whose case had been published.

Focusing on these 12 patients, Dr. Wulfraat and colleagues found that the time from diagnosis of arthritis to diagnosis of IBD ranged from one to 17 years.

The lag from start of etanercept therapy to onset of IBD was considerably shorter, as little as nine days and up to nearly six years.

In most cases, etanercept was stopped, Dr. Wulffraat said. Standard IBD treatments appeared effective, although the disease remained active in about a third of cases. In 75% of the cases the patients developed Crohn's disease.

With the data covering about 2,900 patient-years of etanercept treatment, the incidence of IBD worked out to about 16 cases per 3,000 patient-years.

"This incidence seems very high," Dr. Wulffraat said. However, he pointed out that etanercept could merely be an innocent bystander. He said it was very possible that juvenile arthritis itself may predispose children to other chronic inflammatory diseases.

"We need more precise data, more precise registries," he said. Current registries are maintained by individual countries and their comprehensiveness varies.

Dr. Wulffraat said what is needed is a single, independent, physician-managed, international registry for all biologic drugs in juvenile arthritis patients.

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